Inhibition of the NKp44-PCNA Immune Checkpoint Using a mAb to PCNA.
Animals
Antibodies, Monoclonal
/ pharmacology
Apoptosis
Cell Proliferation
Cytotoxicity, Immunologic
/ drug effects
Head and Neck Neoplasms
/ drug therapy
Humans
Killer Cells, Natural
/ drug effects
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, SCID
Natural Cytotoxicity Triggering Receptor 2
/ antagonists & inhibitors
Proliferating Cell Nuclear Antigen
/ chemistry
Squamous Cell Carcinoma of Head and Neck
/ drug therapy
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Journal
Cancer immunology research
ISSN: 2326-6074
Titre abrégé: Cancer Immunol Res
Pays: United States
ID NLM: 101614637
Informations de publication
Date de publication:
07 2019
07 2019
Historique:
received:
11
01
2019
revised:
09
02
2019
accepted:
30
05
2019
pubmed:
6
6
2019
medline:
10
9
2020
entrez:
6
6
2019
Statut:
ppublish
Résumé
mAb-based blocking of the immune checkpoints involving the CTLA4-B7 and PD1-PDL1 inhibitory axes enhance T-cell-based adaptive immune responses in patients with cancer. We show here that antitumor responses by natural killer (NK) cells can be enhanced by a checkpoint-blocking mAb, 14-25-9, which we developed against proliferating cell nuclear antigen (PCNA). PCNA is expressed on the surface of cancer cells and acts as an inhibitory ligand for the NK-cell receptor, NKp44-isoform1. We tested for cytoplasmic- and membrane-associated PCNA by FACS- and ImageStream-based staining of cell lines and IHC of human cancer formalin fixed, paraffin embedded tissues. The mAb, 14-25-9, inhibited binding of chimeric NKp44 receptor to PCNA and mostly stained the cytoplasm and membrane of tumor cells, whereas commercial antibody (clone PC10) stained nuclear PCNA. NK functions were measured using ELISA-based IFNγ secretion assays and FACS-based killing assays. The NK92-NKp44-1 cell line and primary human NK cells showed increased IFNγ release upon coincubation with mAb 14-25-9 and various solid tumor cell lines and leukemias. Treatment with 14-25-9 also increased NK cytotoxic activity.
Identifiants
pubmed: 31164357
pii: 2326-6066.CIR-19-0023
doi: 10.1158/2326-6066.CIR-19-0023
pmc: PMC7233522
mid: NIHMS1584886
doi:
Substances chimiques
Antibodies, Monoclonal
0
NCR2 protein, human
0
Natural Cytotoxicity Triggering Receptor 2
0
PCNA protein, human
0
Proliferating Cell Nuclear Antigen
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1120-1134Subventions
Organisme : NCI NIH HHS
ID : P30 CA006927
Pays : United States
Informations de copyright
©2019 American Association for Cancer Research.
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